|Publication number||US3907813 A|
|Publication date||Sep 23, 1975|
|Filing date||Sep 30, 1974|
|Priority date||Sep 11, 1973|
|Publication number||US 3907813 A, US 3907813A, US-A-3907813, US3907813 A, US3907813A|
|Inventors||Paul Adriaan Jan Janssen, Bever Willem Florent Maria Van, Raymond Antoine Stokbroekx|
|Original Assignee||Janssen Pharmaceutica Nv|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (2), Referenced by (12), Classifications (10)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent Janssen et al.
[ Sept. 23, 1975 STEREOISOMERIC FORMS OF 4-ANILINO-3-METHYL PIPERIDINES Inventors: Paul Adriaan Jan Janssen,
Vosselaar (Turnhout); Willem Florent Maria Van Bever; Raymond Antoine Stokbroekx, both of Beerse,
all of Belgium Assignee: Janssen Pharmaceutica N.V.,
Beerse, Belgium Filed: Sept. 30, 1974 Appl. No.: 510,268
Related US. Application Data Division of Ser. No. 396,277, Sept. 11, abandoned.
US. Cl. 260/293.79; 424/267; 260/293.77; 260/2938; 260/293.88 lnt. Cl. C07D 211/58 OTHER PUBLICATIONS J. Pharm. Sci., 621983-986, (1973), Riley et al.
Primary Examiner-Sherman D. Winters Attorney, Agent, or Firm-Salvatore R. Conte  ABSTRACT Certain stereoisomers of N-(3-methyl-l-phenethyl-4- piperidyl)propionanilide having very potent analgesic actitivy, methods of preparing same and novel precursors therefor.
13 Claims, N0 Drawings STEREOISOMERIC FORMS OF 4-ANILINO-3-METHYL PIPERIDINES CROSS-REFERENCE TO RELATED APPLICATION ",sAckoRoUND. OF THE mvENTioN The invention pertains to the field of N-( l-phenethyl- 4-piperidyl)propionanilides having a methyl group in the Ii-position of the piperi'dine ring,-'and, more particularly, to certain' geometric and optical isomers thereof. Prior'art compounds unsubstituted inthe 3-position of the piperidine ring,"are described in U.S. Pat. No. 3;l64,600."Methyl substitution in the'3-position is described in J. Pharm. Sci, 62, 983(1973), although no specific preparation or isolation of inherent isomeric components from the optically inactive parent mixture is given. This invention provides for the preparation and isolation "of certairl such isomeric components, novel compositions-thereof and novel precursors therefor. i
SUMMARY OF THE INVENTION There is provided by this invention certain geometric and optical isomers of N-(3-methyl-l-phenethyl-4- piperidyl)propionanilide, which isomers, in base or acid addition salt form, have significantly higher analgesic activity, for example, from about 2-16 times higher potency, based on the weight of base administered, than the prior art compounds disclosed in said U.S. Pat. No. 3,164,600, including the commercially available compound, N-( l-phenethyl-4- piperidyl)propionanilide, also known by its generic name fentanyl. The isomeric forms of this invention may be used in base form or, more conveniently, in acid addition salt form, either alone or in combination with other therapeutically active agents in analgesia.
DESCRIPTION OF THE PREFERRED I EMBODIMENTS The compounds oflthis invention are certain geometric and optical isomers 'of N'('3-methyl-l-phenethyl-4- pipe ridyl )propionanilide Formula I): I
H Me N -CO-Et.
In addition to geometric isomerism, each of the cis" and trans geometric forms canalso occur in the form of optically active dextro and levo isomers (en antiomers) due to the lack of symmetry occassioned by the asymmetric carbons at the 3- and 4-'positions of'the piperidine ring. As used herein, the optical rotation symbol or is an expression of the total rotatory power of the whole molecule corresponding to the sum of the contributions of each such asymmetric carbon atom.
According to this invention, there is provided a' method of synthesizing the geometric isomers (cis and trans) of (I) and the optically active (+(and forms of such geometric isomers. V
The geometric cis and trans isomers of(I) can be prepared by a series of reactions beginning with an initial separation into the corresponding cis and trans geometric isomers of an appropriate 4-anilido-3 -methylpiperidinecarboxylate (II) of the following formula:
wherein R and R each represent a member selected from the group consisting of loweralkyl l-6 carbons) and aralkyl, e.g., a phenylloweralkyl such as, benzyl, phenethyl and the like. Such separation can be accomplished by fractional crystallization techniques employing a suitable ether-alcohol mixture, preferably a mix ture of from about 1:3 to about 3:1 parts by volume of a dialkyl ether and isopropanol. A solution of (II) in such mixtute (warmed sufficiently to provide maximum solubility) is permitted to cool slowly to ambient temperatures (below 35C), whereupon a precipitate of the cis-(i) isomer of (II), free or substantially free of the contaminating trans-(ifisomer, is obtained. Further preferably under reflux. After the reaction is complete,
the excess acid is neutralized with a suitable base, such as, for example, an alkali metal or alkaline earth metal hyroxide, ammonium hydroxide and the like, and the cis-(i)-4-anilino-piperadine product (cis-Ill) is extracted with a suitable organic solvent, such as, for example, an aromatic hydrocarbon (e.g., benzene, toluene, xylene and the like), a halogenated loweralkane (e.g., chloroform, methylenechloride and the like), etc.
, and isolated by conventional techniques. Condensation of (cis-Ill) with an equivalent amount of a reactive ester of phenethylalcohol, such as, halide, sulfonates and the like, preferably PhCH CH -X, wherein X is halo, preferably chloro or bromo, or a radical of fortransmula OSO- R wherein R 2 represents a loweralkyl(- l-6C) or p-tolyl, yields the corresponding.cis-(:)-4-
reaction, preferably under reflux, is carried out in an inert organic solvent, such as, for example, an aromatic hydrocarbon (e.g., benzene, toluene, xylene and the like), a lower alkanone (e.g., 4-methyl-2-pentanone), and the like. The presence of a suitable base, such as, for example, sodium carbonate, is desirable to neutralize the acid (HX) produced during the course of the reaction. The addition of a small amount of potassium iodide may also be added to the reactants when X is halo. The thus-obtained (cis-IV) is then acylated with an appropriate acylating agent, e.g., propionic acid anhydride or halide under standard acylation conditions to yield the desired product (cis-l). Mechanical recovery (e.g., filtration) and standard purification techniques (e.g., recrystallization) of the product offers the essentially pure geometric cis isomer which is free or substantially free of the contaminating trans isomer. The foregoing reaction scheme, which is similarly applicable to the formation of the corresponding trans- (i)isomer, may be illustrated as follows:
Attempts to resolve the aforementioned geometric cis-(i)and trans-(:fisomers of formula (1) into their respective dextro and levo optical isomers by conventional resolution and isolation techniques have not been successful. It has now been found that such optical isomers may be obtained by the synthesis hereinafter described. This synthetic approach is based on an initial resulution of certain novel precursors described in the preparation of the aforementioned geometric isomers, namely, the (i)-4-anilino-3-methylpiperidines of formula(cis-lll)and (trans-lll).
It has been found that said geometric (cis-lll)-(i)- isomer may be resolved by treatment with optically active forms of tartaric acid. At temperatures above approximately 45C both the dextro and levo 4-anilino-3- methyl-piperidines form salts with (+)-tartaric acid which are extremely soluble in lower alkanols (1-6 carbons), preferably methanol, so that minimal amount of alkanol need be employed. The addition of a lower alkanone (l-6 carbons), preferably dimethyl ketone, to heated solutions of said salts till turbidity occurs, results in the crystallization out of solution, as the temperature is lowered below approximately 35C, of the (+)-tartrate salt of cis-()-4-anilino-3- methylpiperidine while the cis-(+) salt stays in solution. Mechanical recovery (e.g., filtration) of the (+)-acid cis(-)-base salt offers an essentially optically pure product which is free or substantially free of contaminating (+)-acid cis-(+)-base salt.
The mother. liquor is concentrated, for example, by evaporation in vacuo, and an aqueous solution of the residue is treated with alkali, for example, an alkali metal or alkaline earth metal hydroxide or ammonium hydroxide, to neutralize the acid that is present. Extraction of the cis-(+)-4-anilino-3-methyl piperidine base is accomplished with chloroform. The chloroform extract is then dried and evaporated and the resultant residue of cis-(+) base is treated with ()-tartaric acid using a lower alkanol and lower alkanone according to the procedure previously described with (+)-tartaric acid. As the temperature of this solution is lowered below approximately 35C, the ()-tartrate salt of cis-()-4- aniline-3-methylpiperidine crystallizes out and is isolated. Said ()-acid cis-(+)-base salt is essentially optically pure and is free or substantially free of contaminating ()-acid cis-()-base salt.
The cis-()-4-anilino-3-methylpiperidine (+)-tartrate and the cis-(+)-4-anilino-3-methylpiperidine tartrate salts obtained by the above resolution procedure may be converted to the corresponding free base by conventional treatment with alkali, and the respective cis()-and cis-(+)-4-anilino-3-methyl piperidines thus obtained may be utilized in the subsequent synthesis of the corresponding cis-(-)- and cis-(+)-isomers of formula (I).
Such synthesis comprises the steps, as previously described in the preparation of the geometric isomers, of condensation with phenethyl halide and subsequent acylation withpropionic acid anhydride or halide.
The foregoing reaction scheme may be illustrated as follows:
Me resolution cis-lll (i) PhCH CH -X HMO-NH I (tartaric acid) Ph cis-lll cis-lll (i) cis-IV cis-l cis-IV cis-l For simplicity the foregoing process has been de- Arzneimittel-Forschung, l3, 502 (1963); 21, 862
scribed for the preparation of cis-(+)-and cis()- (1971), the subject compounds demonstrate. as exemisomers of formulas (l). The process can be operated plified in Table I, an increase in potency of from 2 to in exactly the same way for the formation of the corre- 16 times, as compared against the prototype of the sponding trans-(+)-and trans-()-isomers of formula prior art, fentanyl. (I), except that initial resolution of the geometric (trans-Ill)-(:)-isomer, rather than the (cis-Ill)-(i)- LE 1 isomer, with optically active forms of tartaric acid is required. ED f Potency Duration Accordingly, there are obtained the trans-()-4- compound (wg/kg Rut") anilino3-methyl piperidine (+)-tartrate and fienmnyl Q02 (1) 42 trans-(+)-4-anilino-3-methyl piperidine ()-tartrate g -12L 8-83 g 25 salts, which upon treatment with suitable base, yield 0100125 ,5 86 the corresponding free base forms.
The formula ll precursors may be obtained by treat- 25 It a f gf g fi p1, Td ene ipcn ['0 l nanll 8. lng an pp p "p p of fOrmulaGl'a) cis-(i)-N-(3-methyl-l-pheneihyl-4-piperidyl)propiunanilide oxalate wherein R i a member elected from the group onsist- C. trans-(t)-N-(3-methyl-l-phenethyl-4-piperidyl)propiununilidc oxalate Schiff base(Il-b) which is then subjected to reduction,
for example, with sodium borohydride, to yield the 4- The preferred isomeric forms are the cis isomers, anilino product (II-c) which in turn is acylated with an namely, the cis-(i)- and cis-(+)-forms of N-(3-methylappropriate acylating agent, e.g., a lower alkanoic acid l-phenethyl-4-piperidyl) propionanilide, the latter or aralkanoic acid anhydride or halide, under acylating being most preferred in view of its very marked and conditions familiar to those skilled in the art to yield surprisingly potent analgesic activity.
the desired precursor (II). The reaction scheme may be In view of their useful analgesic activity, the subject illustrated as follows: compounds may be formulated into various pharma- /Me Me Schiff base ROOCN =0 H N- ROOC =N formation (ll-a) (ll-b) Ph Me Me acylation ROOC-- NH 9 ROOC--O-NCOR, (NaBHJ I Ph Ph (ll c) (ll) The organic bases of formula (I) may be converted ceutical forms for administration purposes. To prepare to corresponding pharmaceutically acceptable acid adthe pharmaceutical compositions of this invention, an dition salts by reaction with an appropriate acid, e.g., analgesically effective amount of the particular coman inorganic acid such as, for example, hydrochloric, pound, in base or acid-addition salt form, as the active hydrobromic, hydriodic, sulfuric, nitric and like acids, ingredient is combined in intimate admixture with a or, e.g., an organic acid such as, for example, acetic, pharmaceutically acceptable carrier, which carrier may propionic, glycolic, lactic, oxalic, malic, malonic, tartake a wide variety of forms depending on the form of taric citric, sulfamic, ascorbic and like acids. In turn, pr paration desired for administration. These pharmathe acid addition salts may readily be converted to the ceutical compositions are desirable in unitary dosage corresponding base forms by conventional treatment form Suttable, p y, for admmlstfatlon orally, with suitable base. tally or by parenteral injection. For example, in prepar- The compounds of formula (I), in b f or more ing the compositions in oral dosage form, any of the preferably in the form of a pharmaceutically accept- 5 usual pharmaceutical media may be employed, u as, able acid addition salt, are highly potent analgesics, as for example, water, glycols, oils, alcohols and the like demonstrated, for example, in experimental animals. in the case of oral liquid preparations such as suspen- According to the rat tail withd a al test described in sions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in admini tration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, ma be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution,'glucose solution or a mixture of saline and glucose solution. Injectable suspensionsmay also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Acid addition salts of(l), due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
it is especially advantageous to formulate the afore mentioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predeterspoonfuls and the like, and segregated multiples thereof. The amount of active ingredient per dosage unitwill be from about 0.001 mg to about 1 mg, and, preferably, from about 0.003 mg to about 0.1 mg.
The following formulations exemplify typical analgesic pharmaceutical compositions in dosage unit form suitable for administration to animal and human subjects in accordance with the instant invention.
Capsules: 10,000 Hard gelatin capsules, each containing as the active ingredient (A.l.) 0.05 milligrams of I cis-(t)-N-(3-methyl-l-phenethyl-4- piperidyl)propionanilide, are prepared from the following formulation:
Grams A.[. 0.5 Lactose 999.5 Starch 250 Talc 250 Calcium Stearate A uniform mixture of the active and supplementary ingredients is prepared andfilled into two-piece hard gelatin capsules.
Tablets: 5,000 Compressed tablets, each containing as the active ingredient 0.1 milligrams of trans-(i)-N- (3,-methyll -phenethyl-4-piperidyl propionanilide, are prepared from the following formulation:
Grams A.l. 0.5 Starch Dihasic Calcium phosphate hydrous 5495 Calcium Stcarate 2.5
'piperidyl)propionanilide as the active ingredient per teaspoonful (5mls.
Grams Sucrose Dioctyl sodium sulfosuccinate Bentonite Methyl paraben Propyl paraben Antifoam A. F. Emulsion Propylene glycol FD&C Yellow No. 5
Sodium cyclamatc Sodium saccharin Filtered purified water, q.s., ad 5 liters Dissolve the parabens in the propylene glycol and add this solution to a solution of the sodium cyclamate, sodium saccharin and sucrose in half the water. Suspend the bentonite in hot (about C.) water and stir for 60 minutes. Add the bentonite suspension to the former solution. I
Dissolve the sulfosuccinate in some water and dissolve the Al. in the resulting solution. Add the Antifoam A.F. Emulsion which has been diluted to a lotion consistency with a minimum amount of water and mix well.
Add the latter solution of A.I. to the former mixture and mix well. Add the FD&C Yellow No. 5 dissolved in a small amount of water. Add the orange flavor, q.s. to volume with water, and stir to a homogeneous mixture. Pass the mixture through a colloid mill and fill suitable containers.
Injectable solution: The following formulation provides 1 liter of a parenteral suspension comprising 0.031 mg of trans-(i)-N-(3-methyl-l-phenethyl-4- piperidyl)propionanilide oxalate as the active ingredient per milliliter:
Grams/l A.l. 0.03l Methyl paraben 0.250 Propyl paraben 0.025
Water for Injection. U.S.P., w.s. ad I liter for injection to a total volume of 100 liters. Let stand the solution to cool for at least 12 hours, then correct the volume by addition of water for injection. After mixing, sterilize the solution by filtration (U. S.P. XVll p. 81 1) and fill in sterile containers. Sterilization may also be effected by heat. (USP. XVII p. 810 20 minutes at 121C).
Suppository: Hundred suppositories, each containing 0.05 4 mg of cis-(+)-N-(3-methyl-l-phenethyl-4- piperidyl)propionanilide are prepared from the follow ing formulation:
Grams A.I. 0.005 Theobromu oil 500 Grams A]. 0.1 Lactose 699.9 Talc 150 Starch 150 Calcium Steurate Tablets: 5,000 compressed tablets containing as the active ingredient 0.01 mg of cis-(+)-N-(3-methyl-1- phenethyl-4-piperidyl)propionanilide or a salt thereof as the active ingredient are prepared according to the following formula. The ingredients in fine powder are mixed and granulated with 10% starchpaste. The granules are dried and compressed into tablets.
Grams Al. 0.05 Starch 75 Dibasic Aqueous Calcium-phosphate 574.95
Calcium Stearate The optically inactive compounds of formulas 11 and ll-C, as well as the geometric cis and trans isomers, each free or substantially free of the other, of formulas ll, llland IV, and the optically active (-1-) and isomers of formulas Ill and IV, again each free or substantially free of its opposite enantiomer, are believed to be novel compounds, and, in view of their utility as precursors in the syntheses heretofore described, such compounds constitute-an additional aspect of this invention. l
The following examples are intended'to illustrate, but not to limit, the scope of the present invention. Unless otherwise stated, all parts are by weight.
EXAMPLE 1 A mixture of 32 parts of methyl 3-methyl-4-oxo-lpiperidinecarboxylate, 22 parts of aniline, 160 parts of toluene and a few crystals of p-toluenesulfonic acid is stirred and refluxed for 2 hr. 30 min. using a waterseparator. The toluene is evaporated and the residue is distilled, yielding 38 parts of methyl 3-methyl-4- (phenylimino)-lpiperidinecarboxylate; bp. 149-158C at 0.1-0.4 mm pressure.
To a stirred mixture of 38 parts of methyl 3-methyl-4- (phenylimino)-l-piperidinecarboxylate in 130 parts of methanol are added portionwise 5.3 parts of sodium borohydride at a temperature of 30C (slightly exothermic reaction). After the addition is complete, the whole is stirred for 1 hour at a temperature of about 50C. Then there are added about parts of water. The reaction mixture is concentrated to a volume of about parts and the product is extracted with benzene. The extract is dried and evaporated. The oily residue is distilled, yielding (i)-methyl 4-anilino-3-methyll-piperidinecarboxylate as a yellow oil.
A mixture of 248.5 parts of *-)-methyl 4-anilido-3- methyl-l-piperidinecarboxylate, 198 parts of propionic anhydride and 1200 parts of toluene is stirred and refluxed overnight to produce (i)-methyl 3-methyl-4- (N-phenylpropionamide)-piperidine-l-carboxylate in situ. The reaction mixture is cooled, alkalized with diluted sodium hydroxide solution, while keeping the temperature below 30C. The toluene phase is washed twice with water, dried and evaporated. The semi-solid residue of (i)-methyl 3-methyl-4-(N- phenylpropionamide) piperidine-l-carboxylate (formula II) is triturated in 1200 parts diisopropylether, cooled in ice-bath and the product is filtered off, washed with diisopropylether and dried in vacuo, yielding 213.5
parts of products, which is recrystallized twice from a (l :1)mixture of diisopropylether and 2-propanol (fitrates l and 2 are set aside), yielding about 56 parts of cis-(i)-methyl 3-methyl-4-(N- phenylpropionamide )piperidine-l -carboxylate; mp. l53154.3C.
The combined filtrates l and 2 are evaporated. The residue is crystallized from a (1 1) mixture of diisopropylether and 2-propanol; yielding first at room temperature a fraction of about 42 parts of impure cis-(i)- methyl 3-methyl-4-(N- phenylpropionamide)piperidine-l-carboxylate, and on cooling to 0C, a second fraction of about 29 parts of impure trans-(i)-methyl 3-methyl-4-N- phenylpropionamide)piperidine-1-carboxylate. The latter fraction is recrystallized from the same solventmixture, yielding about 20.5 parts of trans-(i)-methyl 3-methyl-4-- -N-phenylpropionamide)piperidine-l-carboxylate; mp. l32.5l34.2C.
EXAMPLE I] A mixture of parts of cis-(i)-methyl 3-methyl-4- (N-phenylpropionamide)piperidine-l-carboxylate and 750 parts of hydrobromic acid solution 48% is stirred and refluxed for 3 hours. The reaction mixture is cooled and alkalized with sodium hydroxide solution. The free base, cis-(:)-4-anilino-3-methylpiperidine, is extracted with toluene, the extract is dried, filtered and evaporated. The oily residue is distilled; yielding 74 parts of cis-(i)-4-anilino-3-methylpiperidine, bp. 140145C at 0.4 mm pressure, which solidifies on standing at room temperature; mp. 54.656C.
A mixture of 11.1 parts of phenethylbromide, l 1.4 parts of cis-(i)-4-anilin0-3-methylpiperidine,, 13. parts of sodium carbonate and 0.5 parts of potassium iodide in 400 parts of 4-methyl-2-pentanone is stirred andrefluxed for 20 hours. The reaction mixture is filtered several times until clear and the filtrate is evaporated.
The oily residue is dissolved in 800 parts of diiso-- propylether. The solution is treated with activated charcoal, filtered and the filtrate is evaporated again, yielding 16.2 parts of cis-(i)-4-anilino-3-methyl-lphenethylpiperidine.
A mixture of parts of cis-(i)-4-anilino-3-methyll-phenethylpiperidine in 320 parts of toluene is dried azeotropically. After cooling to about 40C, there are added 13 parts of propionic anhydride and the whole is stirred at reflux temperature overnight. The reaction mixture is cooled, alkalized with ammonium hydroxide solution and the organic layer is separated. The latter is dried, filtered and evaporated. The residue of cis- (i)-N-(3-methyl-l-phenethyl-4- piperidyl)propionanilide is dissolved in acetone and to this solution is added a-solution of 6.3 parts of oxalic aciddihydrate in acetone. The crystallized salt is filtered off and recrystallized from 2-propanol,vyielding 12 parts of cis-(i)-N-( 3-methyll -phenethyl- 4piperidyl)propionanilide oxalate; mp 163.7C
EXAMPLE III A mixture of parts of trans-(i)-methyl 3-methyl- 4-( N-phenylpropionamide )piperidine- 1 -carboxylate and 300 parts of hydrobromic acid solution 48% is stirred and refluxed for 2 hr. 30 min. The reaction mixture is poured onto crushed ice and alkalized with sodium hydroxide solution 60%. The free base, trans-(i) 4-anilino-3-methylpiperidine, is extracted ,three times with toluene. The combined extracts are dried, filtered and evaporated, yielding 12 parts of trans-(i)-4- anilino-3-methylpiperidine. I
A mixture of 1 1.4 parts of phenethylbromide, 12 parts of trans-(i)-4-anilino-3-methylpiperidine, 8.5 parts of sodium carbonateand 240 parts of 4-methyl-2- pentanone is stirred and'refluxed overnight (about 15 hours). The reaction mixture is filtered and the fitrate is evaporated. The residue of trans-(:)-4-anilino-3- methyl-l-phenethylpiperidine is dissolved in acetone and the solution is acidified with an excess of 2- propanol previously saturated with gaseous hydrogen chloride. The precipitated salt is filtered off and dried,
yielding 7 parts of trans-(i)-4-anilino-3-methyl-lphenethylpiperidine dihydrochloride.
From 7 parts of trans-(i)-4-anilino-3-methyl-1- phenethylpiperidine dihydrochloride the free base is liberated with ammonium hydroxide solution. After extraction with toluene, the extract is dried and filtered. The filtrate is dried azeotropically and after cooling to about 40C, there are added 4.9 parts of propionic anhydride. The whole is. stirred at reflux temperature overnight. The reaction mixture is cooled, alkalized with ammonium hydroxide solution and the aqueous phase is extracted with chloroform. The chloroform extract is dried, filtered and evaporated. The residue of trans-(i)-N-(3-methyl-l-phenethyl-4 piperidyl)propionanilide is dissolved in acetone and'to this solution is added oxalic acid dihydrate dissolved in acetone. Thecrystallized oxalate salt is filtered off, dried and recrystallized from 2-propanol, yielding 1.5 parts of trans-(i)-N-(3-methyl-l-phenethyl-4- piperidyl)propionanilide oxalate; mp. l59.9 C
EXAMPLE IV A mixture of 99 parts of cis-(i)-4-anilino-3- methylpiperidine and 78.15 parts of (+)-tartaric acid is dissolvedin a minimal amount of methanol. To this boiling solution is added dimethyl ketone. till turbid. Filtration affords 70 parts of the (+)-tartrate salt of cis- ()-4-anilino-3-pipecoline, which can be converted to the free base by treatment with alkali (e.g., 50% NaOH).
The filtrate is concentrated in vacuo and the residue is dissolved in water. The solution is alkalized with a 50% sodium hydroxide solution and extracted three times with chloroform. The extracts are dried and evaporated in vacuo. The residue is dissolved in a minimal amount of methanol together with 45.26 parts of ()-tartaric acid. To this boiling solution is added dimethyl ketone till turbid. Upon cooling, the precipitated ()-tartrate salt of cis-(+)-4-anilino-3- methylpiperidine ;is filtered off and converted into the free base with 50% NaOH. After the extraction of the free base with chloroform, the latter is dried and evaporated in vacuo to yielda residue of 33 parts of cis-(+)- 4-anilino-3-methylpiperidine; a(4% in methanol): +6.l; m.p. 93.594.5C.
EXAMPLE V A mixture of 625 parts of phenethylbromide, 5.55 parts of cis-(+)-4-anilino-3-methylpiperidine, 6.5 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, filtered and the filtrate is evaporated in vacuo. The residue of cis-(+)-4-anilino-1-phenethyl-3- methylpiperidiheis converted into the hydrochloride salt in2propanol; a mixture of the monoand dihydrochloride salt is obtained. The free base is liberated by conventional treatment'with alkali (50% NaOl-l) yielding 5.6' parts of cis-(+)--4-anilino-l-phenethyl-3- methylpiperidineia. (4% in methanol): -+44.8
A mixture of 14.5 parts of cis-(+)-4-anilino-lphenethyl-3-methylpiperidine, 7.8 parts of propionic and anhydride and v400 parts of toluene is stirred and refluxed overnight (about 15 hours). The reaction mixture is cooled, alkalized and extracted with aqueous ammonia. The organic phase is washed twice with water, dried and evaporated in vacuo. The residue of cis- (+)-N-( 3-methyll -phenethyl-4- piperidyl)propionanilide is converted into the nitrate salt in diisopropylether. The salt is filtered off and crystallized from a mixture of diisopropylether and 2- propanol, yielding 19. parts of cis-(+)-N-(3-methyl-1- phenethyl-4-piperidyl)propionanilide nitrate isopropyl alcoholate; mp. 954C; ago +0.2. (2% in methanol).
A mixture of 2.9 parts of cis-(+)-4-anilino-1- phenethyl-3-methylpiperidine, 2.6 parts of propionic anhydride and 200 parts of toluene is stirred and refluxed overnight. The reaction mixture is cooled and water is added. The whole is alkalized with ammonium hydroxide solution and the layers are separated. The aqueous phase is extracted twice with toluene. The combined organic layers are dried, filtered and evaporated in vacuo. The residuev is converted into the oxalate salt. The salt is filtered off and crystallized twice from a mixture of diisopropylether and Z-propanol, yielding 1.8 parts of cis N-(3-methyl-l-phenethyl- 4-piperidyl)propionanilide oxalate; mp. 105.5C; a (4% in methanol): +7.04".
1. A method of resolving cis-(i)-4-anilino-3- methylpiperidine which comprises dissolving cis-(i)-4- anilino-3-methylpiperidine with (+)-tartaric acid in a heated lower alkanol, adding a lower alkanone to said heated solution till turbidity occurs, cooling the solution to below 35C and mechanically separating the insoluble cis-(-)-4-anilino-3-methylpiperidine (+)-tartrate salt.
2. The method of claim 1, wherein said lower alkanol is methanol and said lower alkanone is dimethyl ketone.
3. A method of resolving cis-(:)-4-anilino-3- methylpiperidine which comprises dissolving cis-(i) -4-anilno-3methylpiperidine with (+)-tartaric acid in a heated lower alkanol, adding a lower alkanone to said heated solution till turbidity occurs, cooling the solution to below 35 C, mechanically separating the insoluble cis-()-4-anilino-3-methylpiperidine (+)-tartrate salt, concentrating the mother liguor, neutralizing l1. Cis-(i)-4-anilino-3-methyll phenethylpiperidine.
12. Trans-(:t)-4-anilino-3-methyll phenethylpiperidine.
l3. Cis-(+)-4-anilino-3-methyll phenethylpiperidine.
UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3, 907, 813 Page 1 of 2 DATED September 23, 1975 |Nv ENTOR( Janssen, Paul Adriaarn Jan et a1 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
In Column 2, line 7, the word read H( )H H( )H 5 should In Column 2, line 13, the word (+(-emdshould read and 3 In Column 2, line &8, the word "using; should read Using "piperadine" should read 59, the word In Column 2, line piperidine;
In Column 3, line I, the word "R should read R2;
In Column 3, line 49, the word "resulution should read resolution;
In Column 4, line 23, the word second occurrence to I a In Column 5, line 12, the word cis(-)" should read In Column 5, line 21, the word "anilino3" should read anilino-3g In Column line 60, the word"tartaric citric" should read tartaric, citric;
In Column 7, line 9, the word "ma be" should read may be;
r r I i UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,907,813 Page 2 of 2 DATED September 23, 1975 INVENTOR(S) Janssen, Paul Adriaan Jan 'et a1 It is certifiedthat error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
In Column 8, line 58, the word "w.s. should read In Column 10, line 39, the word filtrates;
"fi-trates" should. read In Column 11; line 29, the word lpiperidyl" should read l-piperidyl;
Signed and Sealed this twenty-sixth Day of July 1977 [SEAL] Arrest:
RUTH C. MASON Arresting Officer C. MARSHALL DANN Commissioner of Patents and Trademarks
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|WO2006055321A2 *||Nov 7, 2005||May 26, 2006||Boehringer Ingelheim Chemicals, Inc.||Process of making fentanyl intermediates|
|WO2006055321A3 *||Nov 7, 2005||Sep 28, 2006||Boehringer Ingelheim Chemicals||Process of making fentanyl intermediates|
|U.S. Classification||546/223, 514/962, 514/960, 546/226, 546/224|
|Cooperative Classification||Y10S514/96, Y10S514/962, C07D211/58|